Neonatal Encephalopathy: The Relationship to Cerebral Palsy

1. Neonatal Encephalopathy:The Relationship to Cerebral Palsy Jay P. Goldsmith, M.D. Tulane University New Orleans, LA goldsmith.jay@gmail.com

2. Disclosures I have no financial investments, conflicts of interest or other disclosure. I am not a neurologist…

3. “When a man knows he isabout to be hanged…it concentrates his mind wonderfully” Dr. Samuel Johnson (Letter to Boswell, 1777)

4. Cerebral Palsy - Etiology • WJ Little: • Cerebral palsy attributed to difficult deliveries  Little’s Disease (Lancet, 1843) • Sigmund Freud (1894) • Cerebral Palsy represents “symptoms of deeper-lying influences which have dominated the development of the fetus.” (Reported by Collier JS: Pro R Soc Med, 1924)

5. Definitional Problems Perinatal vs. Birth vs. Intrapartum Encephalopathy Asphyxia Hypoxic Ischemic Encephalopathy (HIE) Staging of HIE (Sarnat)

7. Asphyxia: Definition • A significant reduction in oxygen delivery or blood flow resulting in: • Shift to anaerobic metabolism • Acidosis (respiratory and metabolic) • End organ involvement

8. Neonatal Encephalopathy Late preterm or term infant Array of abnormal neurologic findings in the first week of life Abnormal state of consciousness, tone and reflexes Severity: mild, moderate, severe (Sarnat stages)

9. Neonatal Encephalopathy • Defining the attributable exposure and timing of insult often difficult • Often more than 1 factor • Rely on indirect tests of fetal-neonatal responses to various stressors/insults • Clinical markers (Apgar scores, MSAF, etc.) • Indicative of intrauterine stress • Not diagnostic of specific etiology • Not predictive of outcome

10. Terminology: The problem with “Birth Asphyxia” or “HIE” • Often used to describe anyencephalopathicnewborn • Implies causality • May ignore modulating factors that effect injury: • e.g., duration, repetition, intervals (often unknown) • Broad DDx for NE not caused by acute disruptions in oxygen content or blood flow. • Therefore, use of term birth asphyxia has declined Wu YW, et. al, Declining diagnosis of birth asphyxia in CA:1991-2000, Pediatrics 2004 • Is it better to use descriptive terminology?

11. TerminologyDescriptive Terminology • Perinatal depression? • Encephalopathy? • Neonatal encephalopathy (NE) • Describes CNS dysfunction in newborn from all causes • including HIE and BA • General Diagnostic criteria: (ACOG, 2003) • Disturbed CNS function in newborn ≥ 35 wk GA • Abnormal level of consciousness or seizures • Often with abnl tone, reflexes and/or respiration

12. Multiple etiologies for NE • Hypoxia-Ischemia • Developmental abnormalities • Metabolic abnormalities • Autoimmune disorders • Coagulation disorders • Infections • Trauma • IUGR • Multiple gestations • Antepartum hemorrhage • Chromosomal abnormalities • Persistent breech/transverse lie

13. Terminology “NE” vs. “HIE” – two points of view • Use of term “HIE” discouraged because: • Dx requires cerebral O2 and blood flow measures • Usually cannot determine when HIE is the cause of NE • Etiologic labels unnecessary when descriptions suffice • Obstacles for research (implies pathogenesis known) • Used as evidence against providers months/years later: • “for not having done the c-section 20 min earlier” • Dammann O, Ferriero D and Gressens P. Neonatal encephalopathy or Hypoxic-Ischemic Encephalopathy? • Appropriate Terminology Matters; Peds Res 2011; 70(1).

14. Terminology “NE” vs. “HIE” – two points of view • Is use of term “HIE” appropriate in some cases? • “NE” is vague term (“neither sufficient nor specific”). • Use term that “best characterizes” disorder. • MRI delineated topography of lesions highly correlated with human and animal neuropathology of perinatal HI. • “HIE” describes NEmeeting clinical features consistent with perinatal HI insult coupled with specific patterns of injury on MR. • Volpe JJ. Neonatal encephalopathy: an inadequate term for HIE; Ann Neurol2012 (72)

15. History: ACOG publications • Technical Bulletin #163 (1992) • Attempt to define markers which would identify NE resulting from intrapartum asphyxia • Model: partial prolonged asphyxia • Essential Criteria (patient had to meet all 4) • Fetal acidemia (pH < 7.00) • Low Apgar Scores (< 3 for >5 minutes) • Neonatal encephalopathy • Multi-system organ dysfunction

16. ACOG Technical Bulletin #163:1992 • Best single marker: Apgar Score < 3 for >20 minutes • Did not identify etiology or timing • Individually, no single criteria sensitive or reliable predictors of ND disability • Only described partial prolonged asphyxia

18. A Proposal for a New Method of Evaluation of the Newborn Infant1 • Five parameters, scores of 0-2: • Color, Heart rate, Reflex irritability, Tone, Respiratory effort • Practical “epigram” of the Apgar Score2: • A: Appearance (color) • P: Pulse (heart rate) • G: Grimace (reflex irritability) • A: Activity (tone) • R: Respiratory effort 1Virginia Apgar. ANESTH ANALG 1953;32:260-265. 2L. Joseph Butterfield. JAMA 1962;208:353.

19. Resuscitated Assisted Apgar Scores: AAP, 2006

20. New data: 1992-2003 • Obstructed cord gases not consistent with status of baby at birth • Brain imaging helpful in determining broad windows of timing • Different types of intrapartum asphyxia • Acute near total asphyxia: may have no significant multi-system organ effects • Different areas of brain affected by type of insult

21. Published 2003

22. Evidence Evaluation • US Preventive Services Task Force: Levels of Evidence (Human) • I: At least 1 randomized controlled trial (RCT) • II-1: Well designed trials without randomization • II-2: Well designed cohort or case controlled studies • II-3: Multiple time series with or w/o intervention • III: Opinions of respected authorities

23. Criteria to Define an Acute Intrapartum Hypoxic Event as Sufficient to Cause Cerebral Palsy NECP, Chapter 8, 2003 • Essential criteria (must meet all four) • Metabolic acidosis (pH < 7.0 and base deficit  12 mmol/L) • Early onset of severe or moderate encephalopathy • Cerebral palsy of the spastic quadriplegic or dyskinetic type • Exclusion of other identifiable etiologies

24. Criteria to Define an Acute Intrapartum Hypoxic Event as Sufficient to Cause Cerebral Palsy • Criteria that collectively suggest intrapartum timing but are nonspecific to asphyxial insults • Sentinel hypoxic event (immediately before or during labor) • Sustained fetal bradycardia or absence of variability with persistent late or variable decelerations when the pattern was previously normal • Apgars 0-3 > 5 minutes • Multisystem organ involvement within 72 hours of birth • Early imaging showing acute nonfocal cerebral abnormality NECP, Chapter 8, 2003

25. NECP 2003: Chapter 8 • Criteria Required to Define an Acute Intrapartum Hypoxic Event as Sufficient to Cause Cerebral Palsy • 72 References • No level I or level II-1 evidence

26. New Data: 2003-2013 • Placental pathology provides important clues to etiology of brain injury • New categorization of intrapartum fetal monitoring by NIH • MRI imaging, especially DWI, helps further delineate timing of injury • New evidence on etiology of stroke • Therapeutic hypothermia improves outcome of recently caused moderate encephalopathy but uses different criteria for initiation

27. The New NECP Task Force • Chairperson: Dr. Mary D’Alton, Columbia University • Representatives: ACOG, AAP, SOGC, RCOG, SMFM, AAFP, NICHD, CNS, AWHONN, others • Charge: To write an update of NECP #1 (2003) • Two additional chapters: • Neuroradiology • Placental Pathology • Publication date: April 2014

28. Published April 2014

29. The New Criteria: Encephalopathy • Neonatal encephalopathy (not HIE) • Define encephalopathy • No encephalopathy→notintrapartum in origin • Multiple causes for neonatal encephalopathy • If HIE, then • Cause • Timing

30. Neonatal Encephalopathy and Outcomes Most encephalopathic newborns do not develop CP Most children with CP do not have NE 50% of fetal-neonatal strokes are asymptomatic in neonatal period Absent NE, highly unlikely that intrapartum events caused ND disability

31. The New Criteria: Questions • Diffuse injury vs. stroke (stroke may not have encephalopathy at birth) • Cerebral palsy vs. other neurodevelopmental disabilities (i.e MR by itself?) • Must motor disability be present to diagnose intrapartum HIE?

32. Diagnostic Evaluation of Encephalopathy • A term or late preterm newborn displaying encephalopathic behavior should have a complete evaluation • Identify cause • For appropriate care • Useful for prognosis • Safety issues for the delivering facility

33. Neonatal Encephalopathy: Clinical Signs • Altered states of arousal • Seizures • Abnormalities of muscle tone/strength • Focal neurologic deficits Signs do not suggest causal nature or timing of injury

34. Neonatal Encephalopathy: PathologicProcesses Genetic Developmental Metabolic-toxic Infectious Traumatic Neoplastic-infiltrative Hypoxia-ischemia

35. Evaluation of Neonatal Encephalopathy • Pregnancy and family history • Fetal tolerance to labor (EFM) • Significant intrapartum events (e.g. bleeding) • Placental pathology (by expert) • Umbilical or early arterial blood gases • Neonatal resuscitation and response (Apgar scores) • Physical and neurologic exam over several days • Organ system involvement • Brain imaging (serial); MRI (by expert) • Evaluation for other etiologies

36. Evaluation of NE:Maternal pregnancy and family history • Association of NE with maternal unemployment, no health insurance, family history of sz, infertility treatment • Significant associations with maternal thyroid disease, pre-eclampsia, bleeding, viral illness, post-datism and late or no prenatal care

37. Evaluation of NE:Maternal pregnancy and family history • Fetal growth (clinical and US) • Presence of significant maternal disease • Maternal drug use • Infections during pregnancy • Results of pregnancy screening tests (GTT) • Perception of fetal movement in last weeks of pregnancy • BMI > 35

38. Changes in fetal growth • IUGR • Symmetrical (early, poor px) • Asymetrical (late, better px) • Microcephaly (1 or 2) • Abnormal Ponderal Index Weight (grams) X 100 Length (cm)³ (At term, should be greater than 2.2)

39. Fetal Tolerance of Labor (EFM) • Specific FH patterns are associated with UPI • Absence of variability (BTB) is associated with fetal acidosis • EFM categories (NICHD, 2008) • Category I: No fetal acidosis • Category II: Indeterminate; monitor closely • Category III: fetal acidemia, move to delivery • Abnormal FHM patterns have extremely high false positive rate (~99%) • IP FHM not associated with decrease in CP when compared with patients who had auscultation alone

40. Significant Intrapartum Events • Cord prolapse, ruptured uterus, AF embolus, significant abruption, maternal shock, prolonged shoulder dystocia • May result in significant fetal acidosis • Often not reflected in cord gas due to loss of cardiac function or cord obstruction • Vaginal bleeding: fetal or maternal? • Sentinel event on EFM (bradycardia)

41. Placental pathology • Placenta: the most neglected organ in pathology • Short umbilical cords: associated with fetal akinesia • Chorioamnionitis/funisitis: FIRS, sepsis • Abruption: clot organization • Chronic conditions: chorangiosis, FTV, HEV • Placental findings cannot give precise timing of brain injury

42. Conflicting Data • Epidemiologic studies: Only 8-15% of CP at term is due to intrapartum asphyxia (Nelson, Wu) • Neuroradiologic studies: pattern and timing of 80% of CNS lesions more consistent with injury within 72 hours of birth (Cowan, Miller) • Hypothesis: Certain factors (e.g. placental lesions, infection, poor growth, etc.) decrease the threshold to brain injury

43. Umbilical cord blood gases • Most objective determinant of fetal metabolic acidosis at birth • Respiratory vs metabolic acidosis • Metabolic reflects anaerobic metabolism • Respiratory: causes vasodilation and may be protective • pH < 7.0 • Reflects poor tolerance to labor • Study: 77% of babies with pH <7.00 normal

44. Cordgases.com Second Edition

45. Confusing Blood Gases Cord gases: Arterial vs. venous Reperfusion acidosis Capillary blood gases in the neonate: are they valid?  pCO2 levels: misplaced ET tube, very recent sentinel event or no cardiac output

46. Umbilical Cord Gas Analysis Placenta Umbilical Vein (UV) (from Placenta to Fetus) Umbilical Artery (UA) (from Fetus to Placenta) • UA pH .02 - 0.06 Units < UV • UA cannot have pO2 > 32-34 mmHg • “No flow” phenomenon • Clamped cord pHa .02 Units/20 mins.

48. Ross and Gala BE algorithm:Assumptions • Fetus enters labor with BE of -2 mmol/L • BE decreases 1 mmol/L for every 3-6 hrs of active labor • BE decreases 1 mmol/L during 2 hours before delivery if significant repetitive decelerations • BE decreases 1 mmol/L/2-3 minutes of severe compromise (uterine rupture or severe terminal bradycardia)

49. Reperfusion Acidosis • Neonatal ABG worse than cord blood gas • Does this mean resuscitation is poor? • During acidosis, blood vessels are constricted and tissues metabolize anaerobically • With resuscitation, tissues are reperfused and acid is brought into central circulation resulting in pH and  base excess • ? Does this phenomenon occur with ventilation alone or is volume (or Na Bicarbonate) required

50. Neonatal Resuscitation and Response • Only 1 in 1000 babies requires CPR/drugs with resuscitation • Most common reasons • Fetal acidosis • Problems with ET tube placement or ventilation • Apparent stillborn (Apgar 0) • Delayed onset of respirations >5 minutes • Cyanosis not important!!!